In recent years, biomolecule measuring devices using semiconductor technologies are drawing attentions. Patent Literature 1 listed below describes a DNA sequencer that cost-effectively and rapidly determines base sequences of deoxyribo nucleic acid (DNA) using pH sensor arrays manufactured with semiconductor technologies. Semiconductor sensors quantify reactions of target biomaterials according to magnitude of electrical signals. Therefore, semiconductor sensors do not require conventional expensive fluorescent reagents and thus are advantageous in terms of costs. It is possible to integrate millions to more than a billion sensors using semiconductor micro-processing technologies. It is also possible to activate each of such sensors in parallel to perform measurements. Therefore, the throughput of the measurement may be readily improved.
Ion Sensitive Field Effect Transistor (ISFET) is one of semiconductor sensors that is frequently used in the field of biomolecule measuring device. Details of ISFET will be described later. ISFET is a device that measures interface potentials induced on ion sensitive layers. Therefore, if there exists electric charges other than those derived from ions to be measured, measuring errors may be caused by such electric charges. However, plasma processing or ion injection are performed during manufacturing the device in semiconductor processes, thus it is likely that electric charges are accumulated in the device. Regarding that technical problem, Non Patent Literature 1 listed below describes that electric charges are accumulated especially at ion sensitive layers, protection layers, interfaces of electrodes, floating electrodes, or gate oxides. Non Patent Literature 2 listed below describes that such accumulation of electric charges may offset threshold voltages of ISFET by around ±10V.
It is known that ISFET has a technical problem referred to as drift in which characteristics shift during measurement process. Drift is a phenomenon caused by chemical reactions between ion sensitive layers and reagents during measurement process which causes the ion sensitive layer to trap electric charges. The amount of drift significantly depends on manufacturing process of the device or device structures. Non Patent Literature 3 listed below describes that the threshold voltage of transistor shifts at a rate of approximately 10 mV/hour.
The offset or drift of threshold voltage due to trapped charges may cause measuring errors and thus it is necessary to reduce them. Patent Literature 1 listed below describes, as a conventional technique for removing trapped charges, a method to irradiate ultraviolet ray to provide electric charge with energy, thereby withdrawing the charge from the device. Non Patent Literature 4 listed below describes that it is necessary to irradiate ultraviolet ray for long hours, e.g. for 10 hours. Non Patent Literature 1 describes that hot electron injection may reduce variations in threshold voltages due to trapped charges.
Another technical problem in utilizing ISFET for measuring biomolecules is that ISFET also outputs signals in response to variation in ion concentration when replacing reagent solutions. In other words, a signal due to replacing reagent solutions (i.e. background signal) is overlapped with the signal due to variation in ion concentration to be measured. For example, ISFET using Ta2O5 as ion sensitive layer is excellent in hydrogen ion selectivity and sensitivity, and is widely used as the pH sensor array in Patent Literature 1 and the like. However, Non Patent Literature 5 describes that such ISFET also outputs signals in response to potassium chloride ion in the solution.
In order to acquire only the target signal from the signal overlapped with background signals, it is necessary to estimate the background signal and to subtract the estimated background signal from the acquired signal. Patent Literature 2 listed below describes a method for estimating background signals using calculated signal value of ISFET in a reaction well not including biomolecules. When performing parallel measurement using one million to more than one million ISFETs as in the above-described semiconductor DNA sequencer, it is necessary to perform the above-described background processing for all of measured data in all reaction wells. Then the background processing increases the analyzing time. This indicates that the time until the measurement result is acquired is elongated. Therefore, the background processing time should be reduced as far as possible.